1. Field of the Invention
The present invention relates to liposome encapsulated taxol and a method of using the same.
2. Description of the Background Taxol, which is (2aR-(2a.alpha., 4a.beta., 6.beta., 9.alpha.(.alpha.R*, .beta.S*), 11.alpha., 12.alpha., 12a.alpha., 12b.alpha.))-.beta.-(.beta.-(benzoylamino)-.alpha.-hydroxybenzenepropanoic acid 6, 12b-bis(acetyloxy)-12-(benzoyloxy)-2a, 3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-dodecahydro-4, 11-dihydroxy-4a, 8, 13, 13-tetramethyl-5-oxo-7, 11-methano-14-cyclodeca (3, 4) benz (1, 2-6) oxet-9-yl ester, has the formula (I): ##STR1## Taxol was first isolated from the bark of the Pacific yew tree, Taxus breviofolia Taxaceae and has been shown to exhibit significant antineoplastic activity against the intraperitoneally (i.p.) implanted B16 melanoma, L1210 leukemia, P388 leukemia and the human MX-1 mammary tumor xenograft. More recently, it was determined that taxol exhibits tumor shrinkage in 30 to 40% of women with advanced ovarian tumors. Taxol has also shown considerable promise in the treatment of metastatic breast cancer.
Taxol inhibits normal cellular replication in vitro by promoting microtubule assembly and stabilizing tubulin polymers against depolymerization. Taxol functions as a mitotic spindle poison and is a potent inhibitor of cell replication in vitro. Taxol markedly enhances all aspects of tubulin polymerization, initiation and elongation are more rapid.
As noted in clinical trials, taxol has shown sufficient activity against lymphoma, ovarian and breast cancers.
Due to its limited solubility in water, taxol is prepared and administered in a vehicle containing cremophor EL, a polyoxyethylated castor oil, and ethanol in a 50:50 (vol/vol) ratio. This solution is further diluted 1:10 in saline before administration to humans. In clinical trials, a consistent problem of anaphylactoid reaction, dyspnea, hypertension and flushing have been encountered. The cardiac toxicity of taxol is treatment limiting and because of this the patient has to be hospitalized for continuous infusion of the drug.
In addition, the stability of taxol once diluted in saline solution is quite low. The drug degrades within 24 hours and hence handling of dosage for the patients becomes very difficult. In addition, the drug precipitates from dilution and hence an on-line filter is utilized for the infusion of drug to the patients.
Attempts to prevent taxol cardiotoxicity and anaphylactoid reaction have included reliance on pretreatment of patients with antihistamine and corticosteroids, and by prolonging the infusion time from six to twenty four hours. Even with these manipulations, patients suffer from serious toxicities which are often fatal.
Further, taxol has conventionally been obtained from Pacific yew trees in forests of the Pacific Northwest, requiring the sacrifice of about six trees to obtain a sufficient quantity of drug to treat one patient. Although it was recently announced that taxol could be produced synthetically, see The Wall Street Journal, Mar. 18, 1992, the yield is necessarily small due to the large number of steps involved in the synthesis.
Thus, even if improved syntheses of taxol could be devised, a number of drawbacks inherent in taxol use remain.
Thus, a need exists for a means by which the above drawbacks may be avoided or their impact minimized.